Respiratory Disease and Smoking May Both Increase Risk of Rheumatoid Arthritis

Across a range of studies, cigarette smoking has been identified as one of the most robust environmental risk factors for the development of rheumatoid arthritis (RA).¹ Findings have demonstrated a dose-dependent increase in the risk of RA among smokers vs never smokers, with 1 meta-analysis showing a 26% increase (relative risk [RR], 1.26; 95% CI, 1.14-1.39) with 1 to 10 pack-years of smoking and a 94% increase with more than 20-pack years of smoking (RR for 21-30 pack years, 1.94; 95% CI, 1.65-2.27).²

While the increase in RA risk was observed regardless of autoantibody status, an even greater risk was found in smokers who were rheumatoid factor (RF)-positive (RR, 2.47; 95% CI, 2.02-3.02) compared with those who were RF-negative (RR, 1.58; 95% CI, 1.15-2.18).²

Smoking, RA, and Antibody Status

“Smoking is a strong risk factor for seropositive RA characterized by elevation of RA-related antibodies such as anti-citrullinated protein antibodies (ACPA),” according to Jeffrey A. Sparks, MD, MMSc, assistant professor of medicine and director of immuno-oncology and autoimmunity in the Division of Rheumatology, Inflammation, and Immunity at Brigham and Women’s Hospital of Harvard Medical School in Boston, Massachusetts. “It is thought that inflammation in pulmonary mucosa and airways may trigger immune tolerance loss that results in antibody production that eventually leads to rheumatoid arthritis,” Dr Sparks told us in an interview.

In a 2018 case-control study including 3655 RA patients and 5883 matched controls, investigators reported a dose-dependent increase in the risk of both ACPA-positive (odds ratio [OR], 1.9; 95% CI, 1.7-2.1) and ACPA-negative RA (OR, 1.3; 95% CI, 1.2-1.5) among smokers. However, the risk of ACPA-positive RA was more pronounced and persisted for years after smoking cessation. “Preventive measures in order to reduce smoking are essential and may result in a decline in RA incidence,” the authors concluded.³

Additionally, other study results have indicated that smoking can influence the response to treatment with disease-modifying antirheumatic drugs (DMARDs) in RA, further underscoring the importance of smoking cessation for patients with RA as well as individuals at risk of developing the disease.¹

Respiratory Disease and RA Risk

Studies have also shown a bidirectional association between respiratory diseases and RA development, and recent findings suggest that smoking may not mediate this relationship.⁴ In a matched cohort study of 283 pre-RA women and 842 control individuals that was published in April 2021 in Arthritis Care and Research, Sparks and colleagues “found that women with airways diseases such as chronic obstructive pulmonary disease (COPD) and asthma were more likely to have elevated ACPA years before clinical presentation of RA,” compared with control participants, said Dr Sparks in the interview.⁵ “In particular, COPD was strongly associated with elevated pre-RA ACPA, and this finding was not solely explained by smoking.”

After adjusting for smoking pack-years and other covariates, pre-RA ACPA positive was associated with an increased risk of COPD (HR, 3.04; 95% CI, 1.33-7.00). The HR for the risk of asthma with pre-RA ACPA positive was 1.74 (multivariable 95% CI, 0.72-4.24), similar to that observed for pre-RA ACPA negative (HR, 1.65; 95% CI, 1.11–2.46).⁵

In a study published in January 2021 in Arthritis and Rheumatology, Kronzer et al analyzed data based on 1631 patients with RA and 3283 matched control individuals from the Epidemiological Investigation of Rheumatoid Arthritis study to examine associations between RA and RA serostatus, respiratory disease, and smoking.

Their findings revealed an elevated risk of both seropositive and seronegative RA in individuals with respiratory diseases as follows (95% CI for all): adjusted OR [aOR], 1.2 (0.8-1.7) for acute upper respiratory disease, 1.4 (1.1-1.9) for chronic upper respiratory disease, 2.4 (1.5-3.6) for acute lower respiratory disease, and 1.6 (1.5-3.6) for chronic lower respiratory disease.⁶

“These associations were present irrespective of RF or ACPA status, though the association was somewhat stronger for ACPA-positive or RF-positive RA than for ACPA-negative or RF-negative RA,” wrote Kronzer et al. In addition, the link between respiratory disease and RA was stronger for nonsmokers (aOR, 2.1; 95% CI, 1.5-2.9) compared to smokers (aOR, 1.2; 95% CI, 0.9-1.5), pointing to the possibility that “smoking and airway disease are associated with RA development through partly different mechanisms.”⁶

Future Directions

Kronzer et al stated that future research should explore potential differences in clinical characteristics between RA patients with each type of exposure, and stratifying study participants by smoking status could reveal novel insights regarding RA risk factors and pathogenic mechanisms. They also noted that efforts to prevent respiratory diseases may be equally important to smoking cessation in preventing the development of RA in at risk individuals.⁶

To that end, “Clinicians should be aware that airway disease could be a risk factor for elevated ACPA and future risk of RA, and patients with airway disease should be monitored for RA development,” Dr Sparks advised. “Research is needed to understand the biologic mechanisms explaining this risk and to identify whether this may lead to prevention strategies.”

Reference

1. Ishikawa Y, Terao C. The impact of cigarette smoking on risk of rheumatoid arthritis: a narrative review. Cells. 2020;9(2):475. doi:10.3390/cells9020475

2. Di Giuseppe D, Discacciati A, Orsini N, Wolk A. Cigarette smoking and risk of rheumatoid arthritis: a dose-response meta-analysis. Arthritis Res Ther. 2014;16(2):R61. doi:10.1186/ar4498

3. Hedström AK, Stawiarz L, Klareskog L, Alfredsson L. Smoking and susceptibility to rheumatoid arthritis in a Swedish population-based case-control study. Eur J Epidemiol. 2018;33(4):415-423. doi:10.1007/s10654-018-0360-5

4. Friedlander HM, Ford JA, Zaccardelli A, Terrio AV, Cho MH, Sparks JA. Obstructive lung disease and risk of rheumatoid arthritis. Expert Rev Clin Immunol. 2020;16(1):37-50. doi:10.1080/1744666X.2019.1698293

5. Zaccardelli A, Liu X, Ford JA, et al. Elevated anti-citrullinated protein antibodies prior to rheumatoid arthritis diagnosis and risks for chronic obstructive pulmonary disease or asthma. Arthritis Care Res (Hoboken). 2021;73(4):498-509. doi:10.1002/acr.24140

6. Kronzer VL, Westerlind H, Alfredsson L, et al. Respiratory diseases as risk factors for seropositive and seronegative rheumatoid arthritis and in relation to smoking. Arthritis Rheumatol. 2021;73(1):61-68. doi:10.1002/art.41491